Abstract. Neonates are susceptible to a variety of infectious diseases that cause significant morbidity and mortality. Over four million infants less than 6 months of age succumb to infectious disease every year. Although vaccines against many of these diseases, such as influenza, are available, many of them either do not work in infants or require multiple boosts to obtain optimal protection. In addition, it is clear that some types of immune responses in neonates can program the immune system to become either more resistant or more susceptible to developing atopic responses, such as allergies or asthma, later in life. The mechanisms underlying poor (or altered) immune outcomes in neonates are thought to include altered inflammatory responses to microbial products, delayed maturation of dendritic cells (DCs) and immature B and T cell compartments that may have repertoires and functions that differ dramatically from those in adults. Moreover, lymphoid organs such as lymph nodes, Nasal Associated Lymphoid Tissue (NALT) and Bronchus Associated Lymphoid Tissue (BALT) are structurally immature in neonates and lack the proper architectural elements that are necessary for efficiently priming T cells, supporting germinal centers and generating high-affinity antibody responses. However, it is not known how each of these differences contributes to altered immune function in neonates. Therefore, it is essential that we first determine how the neonatal immune system functions in the context of influenza infection and then design vaccines to elicit long-lived protective immune responses in neonates. The experiments in this proposal will first determine the mechanisms responsible for poor immune responses to influenza in neonates, particularly regarding immature lymphoid tissues and architecture. In addition, these experiments will test the ability of recombinant influenza vaccines expressing cytokines and chemokines involved in lymphoid organ maturation to elicit robust and long-lived immune responses in neonates. Finally, the experiments in this proposal will determine the mechanisms responsible for the sustained alterations in immune responses following pulmonary inflammation or infection in neonates. Together, these experiments will define the unique features of neonatal immunity and will determine how to overcome some of the immune defects responsible for excessive morbidity and mortality of this population in response to pulmonary infections.